The aim of this Program Project is to develop reliable and rational procedures to repair or replace neurotransmitter function in aged, cognitively impaired animals, with the idea that the tools and strategies developed and tested will be relevant to Alzheimer's disease (AD). Our underlying premise is that transfer to the brain of genes that will either protect against age-related neuronal cell death, repair neuronal cell damage, or replace missing neurotransmitter function will delay age-related functional decline, or reverse some of the deficits associated with age-related decline. The therapeutic potential of gene transfer as a for neurological disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be seriously considered for clinical application. The Project and Cores in this Program Project have been designed for their relevance in addressing these problems and securing a rational approach to gene therapy in AD. Specifically, Project 1 uses established rat models of cognitive dysfunction to test whether and which gene transfer methods and genes result in long-term functional recovery. Projects 4 and 5 will establish transgenic models of age-related cognitive dysfunction to permit a better understanding of the role of specific neuronal systems in age- related cognitive decline and provide more exacting models to test gene therapy strategies. Project 3 uses primate models as a preclinical test of the results from Project 1, 4, and 5. The information obtained in Project 3 will then be used by Projects, 1, 4, and 5 to better design or modify existing experimental designs to meet the goals of clinically relevant gene therapy. The Cores are designed to support all aspects of the Program Project: 9001 will provide cells, plasmids and vectors; 9002 will assist with surgery, behavioral testing and histology; and 9003 will maintain ES cell lines and assist in the production, generation and maintenance of transgenic animals. The interdependency of resources and skills between Projects and Cores, as well as our past success with a Program Project, supports the use of the Program Project form at as the most efficient and cost effective way to develop and refine gene therapy methods for cognitive dysfunction.